Placenta Feeds Itself to Fetus in Times of Starvation

The placenta has long been thought of as a passive organ that simply enables a fetus to take up nutrients from its mother. But new research in mice shows that when calories are restricted, the placenta steps up to the plate-actively sacrificing itself to protect the fetal brain from damage.

Researchers at Cambridge University, UK, examined what happened to 10 fetuses from 8 mice when their pregnant mothers were deprived of food for 24 hours-as might happen in the wild -- about mid-way through gestation. This point in pregnancy is critical in the development of the hypothalamus, the part of the brain that controls primal urges, including maternal instincts.

Behavioural neuroscientists Kevin Broad and Barry Keverne found that the placenta responded by breaking down its own tissues, recycling proteins inside its cells to provide a steady supply of nutrients to the developing hypothalamus despite the mother's interrupted food intake. Their study is published today in the Proceedings of the National Academy of Sciences.

"We didn't know before that this protection of the fetus goes on," says Keverne. "I expected the lack of food to affect the fetal brain and the placenta equally, but instead we see the placenta acting as an interface to make sure the fetuses' particular stage of brain development is protected."

Imprint of starvation

As well as causing placental breakdown, the enforced starvation had effects on the expression of some 'imprinted genes' in the placenta. Such genes, unique to mammals, are inherited by the fetus in the normal way but their expression is subject to 'epigenetic' chemical tweaks by the mother through the placenta. By silencing either the paternal or maternal copy of the gene, she is able to shape her offspring's genetic destiny during pregnancy.

One of the affected genes was Peg3, which regulates the number of neurons that produce oxytocin, a hormone that is important for maternal care, milk production and giving birth. Peg3 expression in the placenta is normally closely tied with expression of the gene in the fetus's brain. After the mother had gone 24 hours without food, the researchers measured a 35% decrease in Peg3 expression in the placenta. But Peg3 expression in the fetal hypothalamus actually increased.

The researchers say that as with nutrient supply, the fetus appears to be protected from the consequences of the mother's starvation - in this case downregulation of a gene that threatens to impair the next generation's mothering ability and therefore reproductive success.

The main message is that the fetal hypothalamus and placenta "are not independent tissues", says Keverne. "They have evolved together in such a way that built into the system is a genetic flexibility enabling the next generation to be primed to become good mothers."

The researchers didn't study whether the genetic changes in the placenta caused by lack of food then feed back to the mother-to-be, reducing her maternal instincts. But Michael Skinner, an expert in reproductive biology at Washington State University in Pullman, thinks that is possible and would like to see more work in this direction. The placenta, he points out, communicates with the mother's own hypothalamus. "The hormones being produced by the placenta are going to shift the mother's programming," he says. "Whether that will turn around and influence the brain of the mother is all speculation, but if [the starvation] was long enough it might."

Keverne stresses that the findings in mice cannot necessarily be extrapolated to humans-in whom such starvation studies can't be done ethically.

But he wonders whether measuring the expression levels of neural genes in the placenta once a baby is born might provide a window into the brain function of that baby. His experiment also showed changes in expression of over 200 non-imprinted genes in the placenta on food-deprivation. Forty-one of those genes have been associated with neurological disorders, and two have been identified as markers for schizophrenia.

"The brain was rescued by the placenta in this case," he says. "But presumably if the perturbation had been more serious it would have affected the fetus's hypothalamus, which you could pick up by looking at the placenta."

This article is reproduced with permission from the magazine Nature. The article was first published on August 1, 2011.

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